EP0770384B1 - Solid, anhydrous, pharmaceutical compositions for vaginal use - Google Patents

Solid, anhydrous, pharmaceutical compositions for vaginal use Download PDF

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Publication number
EP0770384B1
EP0770384B1 EP96116870A EP96116870A EP0770384B1 EP 0770384 B1 EP0770384 B1 EP 0770384B1 EP 96116870 A EP96116870 A EP 96116870A EP 96116870 A EP96116870 A EP 96116870A EP 0770384 B1 EP0770384 B1 EP 0770384B1
Authority
EP
European Patent Office
Prior art keywords
anhydrous
polycarbophil
active ingredient
vaginal
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96116870A
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German (de)
French (fr)
Other versions
EP0770384A1 (en
Inventor
Celestino Ronchi
Fabio Berlati
Francesco Scaglione
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Monteresearch Srl
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Monteresearch Srl
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Filing date
Publication date
Application filed by Monteresearch Srl filed Critical Monteresearch Srl
Priority to SI9630375T priority Critical patent/SI0770384T1/en
Publication of EP0770384A1 publication Critical patent/EP0770384A1/en
Application granted granted Critical
Publication of EP0770384B1 publication Critical patent/EP0770384B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds

Definitions

  • the present invention relates to pharmaceutical compositions for vaginal use.
  • Bioadhesive polymers have been and still are the subject of in-depth studies. Bioadhesive polymers are generally known for their ability of being bound to biological membranes.
  • products containing a water-insoluble bioadhesive polymer and formulated as an oil-in-water emulsion for the treatment of vaginal dryness are commercially available (REPLENS- by Warner-Lambert Co.).
  • compositions containing bioadhesive polymers and therapeutic agents provide the desired contact between the mucosal membrane and the composition.
  • the composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period.
  • anhydrous solid pharmaceutical composition employing polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle improves residence at the application site and provides a long-lasting effetc.
  • compositions employing water-insoluble mucoadhesive agents containing water are already hydrated and immediately bond to a mucosal membrane upon application. Once applied, the composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period, allowing for local or systemic activity.
  • anhydrous pharmaceutical compositions containing mucoadhesive agents are hydrated only after contact with the mucosa.
  • the preparation When the preparation is applied to the vaginal mucosa, the pharmaceutical form simultaneously disintegrates, forming an adhesive layer on the mucosa containing the active ingredient, allowing for local or systemic activity.
  • the present invention relates to anhydrous solid pharmaceutical compositions for vaginal use with at least one active ingredient comprising polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle.
  • the composition may also contain pharmaceutically acceptable additives. These additives include stabilizers, preservatives, excipients, binders, coloring agents, odor controlling agents and the like.
  • Polycarbophil is a muco-adhesive polymer well known to those skilled in the art.
  • the content of polycarbophil in the composition of the invention ranges from 0.5% to 90% by weight of the composition.
  • the pharmaceutically acceptable vehicle is the bulk substance through which the bioadhesive polymer and the active ingredients (s) are distributed to form a dispersion. This vehicle must also be capable of being used in or on humans or other mammals without causing any ill effects, such as toxicity or severe irritation to the mucosal tissue.
  • Pharmaceutically acceptable vehicles suitable for use in the present invention include powders, solid and semi-solid lipid masses, and anhydrous liquids, normally used in pharmaceutical and cosmetic preparations.
  • the active ingredients suitable for use in the present invention are of different types (natural, semisynthetic and synthetic) and include antimycotic agents, antiprotozoal agents, disinfectants, hormones, antibiotics, chemotherapeutic agents and others) and are generally present in the composition ranging from 0,002% to 90% by weight of the composition.
  • active ingredients used in the present invention are imidazole antimycotics such as miconazole, econazole, ketonazole, local antiseptics and hormones.
  • composition of the present invention may take the form of vaginal tablets, soft gelatin capsules, semi-synthetic glyceride-based suppositories, which may or may not contain surfactant substances and polyethylene glycol-based suppositories.
  • the dosage forms of the invention may be prepared by experts of the art according to well known techniques (see Remington's Pharmaceutical Sciences Handbook, XVII ed., Mack Pub., N.Y., U.S.A.).
  • the sustained release of the drug is regulated by the presence of the muco-adhesive polymer.
  • polycarbophil in the manufacture of anhydrous solid vaginal pharmaceutical compositions with controlled release fall within the scope of the present invention.
  • Example No. 1 Vaginal suppositories containing an antimycotic Econazole Nitrate (active ingredient)
  • Example 2 Vaginal suppositories containing an antimycotic Miconazole Nitrate (active ingredient)
  • Example 3 Vaginal suppositories containing Povidone-Iodine (active ingredient)
  • Povidone-Iodine (Iodine 10%) 200 mg Policarbophyl (Noveon® AA1) 200 mg Polyethylene-glycol mixture q.s. to 3 g
  • Example N. 4 Soft-gelatine capsules containing Estriol (active ingredient)
  • Component Unitary Formula Estriol 0.5 mg Policarbophyl (Noveon® AA1) 50 mg Labrafil® q.s. to 500 mg Gelatin shell q.s.

Abstract

Anhydrous solid pharmaceutical composition for vaginal use, comprising at least one active ingredient in a mixture with conventional carriers and excipients, containing one or more muco-adhesive polymers dispersed in the carrier. These compositions allow for longer contact between the mucosa and the active ingredient and on-site residence, maintaining an effective therapeutic concentration for longer times.

Description

Filed of the Invention
The present invention relates to pharmaceutical compositions for vaginal use.
Background of the Invention
Bioadhesive polymers have been and still are the subject of in-depth studies. Bioadhesive polymers are generally known for their ability of being bound to biological membranes.
Numerous patents have come into being which have as their object the use of muco-adhesives in the form of tablets which contain a bioadhesive layer and a non-adhesive layer containing the medicament (U.S. Patent No. 4,292,299 to the Suzuki, et al.) or controlled release treatment compositions which, when in the presence of sufficient water to swell the bioadhesive, will adhere to skin or to a mucosal membrane (U.S. Patent No. 4,615,697 to J.R. Robinson). Other patents have been developed for muco-adhesive compositions which will bioadhesively attach to a mucosal membrane, but ca be removed by tap water if one wishes. Wang et al. (EP 93305950.3) disclosed the application of polyvinyl pyrrolidone-based muco-adhesive polymers and carboxy-functional polymers (characterized by the presence of carboxyl groups in the chains forming the polymer) dispersed in a pharmaceutically acceptable vehicle, preferably water, in an amount sufficient to form a liquid suspension, preferably a gel.
Moreover, products containing a water-insoluble bioadhesive polymer and formulated as an oil-in-water emulsion for the treatment of vaginal dryness are commercially available (REPLENS- by Warner-Lambert Co.).
Compositions containing bioadhesive polymers and therapeutic agents provide the desired contact between the mucosal membrane and the composition. The composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period.
It has now been found that an anhydrous solid pharmaceutical composition employing polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle improves residence at the application site and provides a long-lasting effetc.
Pharmaceutical forms employing water-insoluble mucoadhesive agents containing water are already hydrated and immediately bond to a mucosal membrane upon application. Once applied, the composition is left in contact with the mucosal membrane for a sufficient time for the treating agent to be released over a controlled period, allowing for local or systemic activity.
On the other hand, anhydrous pharmaceutical compositions containing mucoadhesive agents are hydrated only after contact with the mucosa. When the preparation is applied to the vaginal mucosa, the pharmaceutical form simultaneously disintegrates, forming an adhesive layer on the mucosa containing the active ingredient, allowing for local or systemic activity.
Description of the Invention
The present invention relates to anhydrous solid pharmaceutical compositions for vaginal use with at least one active ingredient comprising polycarbophil as the sole muco-adhesive polymer dispersed in a pharmaceutically acceptable vehicle. In addition, the composition may also contain pharmaceutically acceptable additives. These additives include stabilizers, preservatives, excipients, binders, coloring agents, odor controlling agents and the like.
Polycarbophil is a muco-adhesive polymer well known to those skilled in the art. The content of polycarbophil in the composition of the invention ranges from 0.5% to 90% by weight of the composition.
The pharmaceutically acceptable vehicle is the bulk substance through which the bioadhesive polymer and the active ingredients (s) are distributed to form a dispersion. This vehicle must also be capable of being used in or on humans or other mammals without causing any ill effects, such as toxicity or severe irritation to the mucosal tissue. Pharmaceutically acceptable vehicles suitable for use in the present invention include powders, solid and semi-solid lipid masses, and anhydrous liquids, normally used in pharmaceutical and cosmetic preparations.
The active ingredients suitable for use in the present invention are of different types (natural, semisynthetic and synthetic) and include antimycotic agents, antiprotozoal agents, disinfectants, hormones, antibiotics, chemotherapeutic agents and others) and are generally present in the composition ranging from 0,002% to 90% by weight of the composition.
Examples of active ingredients used in the present invention are imidazole antimycotics such as miconazole, econazole, ketonazole, local antiseptics and hormones.
The composition of the present invention may take the form of vaginal tablets, soft gelatin capsules, semi-synthetic glyceride-based suppositories, which may or may not contain surfactant substances and polyethylene glycol-based suppositories.
The dosage forms of the invention may be prepared by experts of the art according to well known techniques (see Remington's Pharmaceutical Sciences Handbook, XVII ed., Mack Pub., N.Y., U.S.A.).
A study was carried out on a total of 20 healthy female volunteers in order to compare the release rates of econazole nitrate from a conventional drug without a bioadhesive and from three formulations, each containing a different concentration of polycarbophil as mucoadhesive agent (25, 50, and 100 mg/suppository). Vaginal fluid samples were taken at 0 and at 2, 6, 12 and 24 h from administration and drug concentrations measured by HPLC. Results showed slower release rates of econazole nitrate plus the muco-adhesive as compared to the commercially available drug. High vaginal fluid drug concentrations were measured up to 24 h following the administration of the vaginal suppositories containing polycarbophil while no drug was detected 12 h following the administration of the commercially available product.
Econazole levels (mg/ml) in vaginal fluid
Product
Time (hours)		 0 2 6 12 24
Commercial
Product 0 48.6 0.85 0 0
Formulation 1 0 56.4 44.7 36.9 0.12
Formulation 2 0 88.7 54.3 28.9 12.6
Formulation 3 0 96.8 68.3 46.3 18.9
The sustained release of the drug is regulated by the presence of the muco-adhesive polymer.
The use of polycarbophil in the manufacture of anhydrous solid vaginal pharmaceutical compositions with controlled release fall within the scope of the present invention.
The following examples further illustrate the invention.
Example No. 1: Vaginal suppositories containing an antimycotic Econazole Nitrate (active ingredient)
Component Unitary Formula
Econazole Nitrate 100 mg
Policarbophyl (Noveon® AA1) 100 mg
Semi-synthetic Triglicerides (m.p. 37°C) q.s. to 3 g
Example 2: Vaginal suppositories containing an antimycotic Miconazole Nitrate (active ingredient)
Component Unitary Formula
Miconazole Nitrate 100 mg
Policarbophyl (Noveon® AA1) 200 mg
Polyethylene-glycol mixture q.s. to 3 g
Example 3: Vaginal suppositories containing Povidone-Iodine (active ingredient)
Component Unitary Formula
Povidone-Iodine (Iodine 10%) 200 mg
Policarbophyl (Noveon® AA1) 200 mg
Polyethylene-glycol mixture q.s. to 3 g
Example N. 4: Soft-gelatine capsules containing Estriol (active ingredient)
Component Unitary Formula
Estriol 0.5 mg
Policarbophyl (Noveon® AA1) 50 mg
Labrafil® q.s. to 500 mg
Gelatin shell q.s.

Claims (5)

  1. An anhydrous solid pharmaceutical composition for vaginal use with at least one active ingredient comprising polycarbophil as the sole mucoadhesive polymer dispersed in a pharmaceutically acceptable vehicle.
  2. A composition according to claim 1, wherein the amount of polycarbophil is from 0.5% to 90% by weight of the composition.
  3. A composition according to claims 1-2, wherein the active ingredient(s) are selected from the group consisting of antimycotic agents, antiprotozoal agents, disinfectants, hormones, antibiotics, chemotherapeutic agents.
  4. A composition according to claims 1-3, in form of vaginal tablets, soft gelatin capsules, semi-synthetic glyceride-based suppositories, optionally containing surfactant substances and polyethylene glycol-based suppositories.
  5. Use of polycarbophil in the manufacture of controlled release, anhydrous, solid pharmaceutical compositions.
EP96116870A 1995-10-27 1996-10-21 Solid, anhydrous, pharmaceutical compositions for vaginal use Expired - Lifetime EP0770384B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
SI9630375T SI0770384T1 (en) 1995-10-27 1996-10-21 Solid, anhydrous, pharmaceutical compositions for vaginal use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI952221 1995-10-27
IT95MI002221A IT1275816B1 (en) 1995-10-27 1995-10-27 SOLID PHARMACEUTICAL COMPOSITIONS FOR VAGINAL USE

Publications (2)

Publication Number Publication Date
EP0770384A1 EP0770384A1 (en) 1997-05-02
EP0770384B1 true EP0770384B1 (en) 2002-02-06

Family

ID=11372443

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96116870A Expired - Lifetime EP0770384B1 (en) 1995-10-27 1996-10-21 Solid, anhydrous, pharmaceutical compositions for vaginal use

Country Status (9)

Country Link
EP (1) EP0770384B1 (en)
JP (1) JPH09165344A (en)
AT (1) ATE212829T1 (en)
DE (1) DE69619052T2 (en)
DK (1) DK0770384T3 (en)
ES (1) ES2171589T3 (en)
IT (1) IT1275816B1 (en)
PT (1) PT770384E (en)
SI (1) SI0770384T1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1284874B1 (en) 1996-08-02 1998-05-22 Farmigea Spa BIOADHESIVE COMPLEXES OF POLYCARBOPHIL AND AZOLIC ANTIFUNGAL OR ANTIPROTOZOAR DRUGS
US6416779B1 (en) * 1997-06-11 2002-07-09 Umd, Inc. Device and method for intravaginal or transvaginal treatment of fungal, bacterial, viral or parasitic infections
US6624200B2 (en) 1998-08-25 2003-09-23 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets
US8765177B2 (en) 1997-09-12 2014-07-01 Columbia Laboratories, Inc. Bioadhesive progressive hydration tablets
FR2777783A1 (en) * 1998-04-24 1999-10-29 Innothera Lab Sa Pharmaceutical composition for treatment of infectious vulvovaginitis and vaginosis
CN1306444A (en) * 1998-06-19 2001-08-01 奥西比奥公司 Medical device having anti-infective and contraceptive properties
JP4552322B2 (en) 1998-11-17 2010-09-29 大正製薬株式会社 Suppository
US20060105008A1 (en) * 2002-03-28 2006-05-18 Nawaz Ahmad Compositions and methods for reducing vaginal pH
US20040033968A1 (en) * 2002-08-16 2004-02-19 Lin Shun Y. Optimal volume of intra-vaginal semisolid dosage forms for treating vaginal infections
AU2006209263A1 (en) * 2005-09-12 2007-03-29 Mcneil-Ppc, Inc. Anhydrous composition containing an acid-acid buffer system
CA2687310A1 (en) * 2007-05-24 2008-12-04 New York Blood Center Inc. Rapidly dispersible vaginal tablet that provides a bioadhesive gel
ES2344673B1 (en) 2008-08-07 2011-05-03 Italfarmaco, S.A. USE OF ESTRIOL IN THE PREPARATION OF A PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF VAGINAL ATROPHY IN WOMEN WITH RISK OF POTOLOGIATUMORAL.
ES2344675B1 (en) 2008-12-19 2011-04-28 Italfarmaco, S.A. USE OF ESTRIOL IN THE PREPARATION OF A PHARMACEUTICAL FORMULATION FOR THE TREATMENT OF VAGINAL ATROPHY IN WOMEN WITH RISK OF VARIUM VARCOLOGY.
WO2010079373A1 (en) * 2009-01-09 2010-07-15 EGIS GYOGYSZERGYAR, Nyilvánosan, Müködö Improved pharmaceutical formulation
JP6335270B2 (en) * 2013-03-15 2018-05-30 ワーナー チルコット カンパニー， エルエルシーＷａｒｎｅｒ Ｃｈｉｌｃｏｔｔ Ｃｏｍｐａｎｙ， Ｌｌｃ Pharmaceutical soft gelatin capsule dosage form using modified guar gum
AU2014240039B2 (en) * 2013-03-15 2019-01-24 Allergan Therapeutics LLC Pharmaceutical soft gelatin capsule dosage form
CN110237042A (en) * 2019-06-04 2019-09-17 华润双鹤利民药业（济南）有限公司 Miconazole nitrate for vagina piece production technology
MX2020011523A (en) * 2020-10-29 2022-05-02 Exeltis Pharma Mexico S A De C V Pharmaceutical composition suitable for vaginal administration in the form of ovules and use thereof.

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Publication number Priority date Publication date Assignee Title
FR2335203A1 (en) * 1975-12-17 1977-07-15 Marcy Jean Hydrophilic pastes for mucosal treatment - contg. hydrophilic mass, e.g. pectin, and oily binding agent
JPS5562012A (en) 1978-11-06 1980-05-10 Teijin Ltd Slow-releasing preparation
JPS58152809A (en) * 1982-03-05 1983-09-10 Eisai Co Ltd Stable foaming vaginal suppository
AU565354B2 (en) 1983-11-14 1987-09-10 Bio-Mimetics Inc. Bioadhesive compositions and methods of treatment therewith
US4613497A (en) * 1984-02-29 1986-09-23 Health Products Development, Inc. Dry, water-foamable pharmaceutical compositions
IT1247529B (en) * 1991-04-24 1994-12-17 Poli Ind Chimica Spa PHARMACEUTICAL COMPOSITIONS IN FOAM FORM FOR INTRAVAGINAL, SKIN AND ORAL ADMINISTRATION

Also Published As

Publication number Publication date
DE69619052D1 (en) 2002-03-21
DE69619052T2 (en) 2002-11-14
ES2171589T3 (en) 2002-09-16
PT770384E (en) 2002-06-28
ITMI952221A0 (en) 1995-10-27
SI0770384T1 (en) 2002-06-30
ATE212829T1 (en) 2002-02-15
EP0770384A1 (en) 1997-05-02
ITMI952221A1 (en) 1997-04-27
DK0770384T3 (en) 2002-05-21
IT1275816B1 (en) 1997-10-17
JPH09165344A (en) 1997-06-24

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